Deuterium-enriched piperidinonyl-oxoisoindolinyl acetamides and methods of treating medical disorders using same

ABSTRACT

The invention provides deuterium-enriched piperidinonyl-oxoisoindolinyl acetamide compounds, pharmaceutical compositions, and methods of using such compounds and pharmaceutical compositions to treat cancer, angiogenesis disorders, immune disorders, and other medical disorders.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 16/244,218, filed Jan. 10, 2019, which is a continuation ofU.S. patent application Ser. No. 15/720,262, filed Sep. 29, 2017, whichclaims the benefit of and priority to U.S. Provisional PatentApplication Ser. No. 62/402,084, filed Sep. 30, 2016, the contents ofeach of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides deuterium-enriched piperidinonyl-oxoisoindolinylacetamide compounds, pharmaceutical compositions, and methods of usingsuch compounds and pharmaceutical compositions to treat cancer and othermedical disorders.

BACKGROUND

Cancer remains a substantial challenge to human health. Cancer isfrequently characterized by an increase in the number of abnormal cellsderived from a given normal tissue. Exemplary cancers that impact asubstantial percentage of the patient population include, for example,cancer of the lung, colon, rectum, prostate, breast, and blood. Theincidence of cancer continues to increase as the general populationages, new cancers develop, and susceptible populations (e.g., peopleinfected with AIDS) grow. Notwithstanding the significant need forcancer therapy, options for the treatment of cancer are limited. Forexample, in the case of blood cancers (e.g., multiple myeloma), fewtreatment options are available, especially when conventionalchemotherapy fails and bone marrow transplantation is not an option. Asubstantial demand therefore exists for new methods and compositionsthat can be used to treat patients with cancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. One mechanism is thesecretion by tumor cells of cytokines with angiogenic properties.Examples of these cytokines include acidic and basic fibroblastic growthfactor (bFGF), angiogenin, vascular endothelial growth factor (VEGF),and TNF-α. Alternatively, tumor cells can release angiogenic peptidesthrough the production of proteases and the subsequent breakdown of theextracellular matrix where some cytokines are stored. Angiogenesis canalso be induced indirectly through the recruitment of inflammatory cells(particularly macrophages) and the subsequent release of angiogeniccytokines (e.g., TNF-α, bFGF). A variety of disorders are alsoassociated with undesired angiogenesis. Thus, a need exists for improvedmethods and agents for inhibiting angiogenesis.

The present invention addresses these unmet needs and providesadditional advantages.

SUMMARY

The invention provides deuterium-enriched piperidinonyl-oxoisoindolinylacetamide compounds, pharmaceutical compositions, and methods oftreating medical disorders using a deuterium-enriched compound describedherein. Deuterium-enriched piperidinonyl-oxoisoindolinyl acetamidecompounds described herein contain deuterium enrichment at the chiralcenter of the piperidine-2,6-dione group and optionally at otherlocations in the compound. The deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compounds may be provided inenantiomerically pure form. These features are contemplated to providetherapeutic agents with improved properties.

Accordingly, one aspect of the invention provides a deuterium-enrichedcompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. In certain embodiments, thedeuterium-enriched compound is a compound of Formula I-A represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the variables are as defined in thedetailed description. In certain other embodiments, thedeuterium-enriched compound is a compound of Formula I-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the variables are as defined in thedetailed description.

In another aspect, the invention provides a pharmaceutical compositioncomprising a deuterium-enriched piperidinonyl-oxoisoindolinyl acetamidecompound described herein and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of treating a medicaldisorder described herein, such as a disorder selected from the groupconsisting of cancer, an immune disorder, and an inflammatory disorder.The method comprises administering to a patient in need thereof atherapeutically effective amount of a deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compound described herein, suchas a deuterium-enriched compound of Formula I, I-A, I-B, or II to treatthe disorder. In a preferred embodiment, the disorder is cancer.

DETAILED DESCRIPTION

The invention provides deuterium-enriched piperidinonyl-oxoisoindolinylacetamide compounds, pharmaceutical compositions, and methods oftreating medical disorders using a deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compound described herein.Deuterium-enriched piperidinonyl-oxoisoindolinyl acetamide compoundsdescribed herein contain deuterium enrichment at the chiral center ofthe piperidine-2,6-dione group and optionally at other locations in thecompound. Deuterium enrichment at the chiral center reduces the rate atwhich the two enantiomers of the piperidine-2,6-dione group mayinterconvert. Further, the deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compounds may be provided inenantiomerically pure form. These features are contemplated to providetherapeutic agents with improved properties.

Deuterium-enriched refers to the feature that the compound has aquantity of deuterium that is greater than in naturally occurringcompounds or synthetic compounds prepared from substrates having thenaturally occurring distribution of isotopes. The threshold amount ofdeuterium enrichment is specified in certain instances in thisdisclosure, and all percentages given for the amount of deuteriumpresent are mole percentages.

Deuterium (²H) is a stable, non-radioactive isotope of ¹H hydrogen andhas an atomic weight of 2.014. Hydrogen naturally occurs as a mixture ofthe isotopes ¹H hydrogen (i.e., protium), deuterium (²H), and tritium(³H). The natural abundance of deuterium is 0.015%. One of ordinaryskill in the art recognizes that in all chemical compounds with an Hatom, the H atom actually represents a mixture of ¹H hydrogen, deuterium(²H), and tritium (³H), where about 0.015% is deuterium. Thus, compoundswith a level of deuterium that has been enriched to be greater than itsnatural abundance of 0.015% are considered unnatural and, as a result,novel over their non-enriched counterparts.

Exemplary compositions and methods of the present invention aredescribed in more detail in the following sections: I.Deuterium-enriched Piperidinonyl-oxoisoindolinyl Acetamide Compounds;II. Therapeutic Applications; III. Dosing Considerations and CombinationTherapy, and IV. Pharmaceutical Compositions. Aspects of the inventiondescribed in one particular section are not to be limited to anyparticular section.

I. Deuterium-Enriched Piperidinonyl-Oxoisoindolinyl Acetamide Compounds

One aspect of the invention provides deuterium-enriched compounds foruse in the therapeutic methods and pharmaceutical compositions describedherein. As explained above, the deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compounds described hereincontain deuterium enrichment at the chiral center of thepiperidine-2,6-dione group. Deuterium enrichment at the chiral centerreduces the rate at which the two enantiomers of thepiperidine-2,6-dione group may interconvert.

Accordingly, one aspect of the invention provides a deuterium-enrichedcompound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is H or D, provided that the abundance of deuterium in Z is at        least 30%;    -   R^(I-1), R^(I-2), R^(I-3), R^(I-4), R^(I-5), R^(I-6), R^(I-7),        R^(I-8), R^(I-9), R^(I-10), R^(I-11), R^(I-12), and R^(I-13) are        independently H or D;    -   R¹ is optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl or optionally        substituted heterocyclyl;    -   R² and R³ are each halogen;    -   where the substituents on R¹, when present, are one to three        groups Q, where each Q is independently alkyl, halo, haloalkyl,        alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted        cycloalkyl, optionally substituted cycloalkylalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted aryl, optionally        substituted heteroaryl, —R⁴OR⁵, —R⁴O—R⁴—OR⁵, —R⁴N(R⁶)(R⁷),        —R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹, or        —R⁴S(O)_(t)R⁸;    -   R⁴ represents independently for each occurrence alkylene,        alkenylene or a direct bond;    -   R⁵ represents independently for each occurrence hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,        heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,        heteroaryl, heterocyclyl or heterocyclylalkyl groups in R⁵ are        each independently optionally substituted with 1-3 Q¹ groups,        where each Q¹ is independently alkyl, haloalkyl or halo;    -   R⁶ and R⁷ are selected as follows:        -   i) R⁶ and R⁷ are each independently hydrogen or alkyl; or        -   ii) R⁶ and R⁷ are taken together with the nitrogen atom to            which they are attached to form a 5 or 6-membered            heterocyclyl or heteroaryl ring, optionally substituted with            one or two halo, alkyl or haloalkyl;    -   R⁸ is alkyl, haloalkyl, or hydroxyalkyl;    -   R⁹ is alkyl or aryl;    -   J is O or S; and    -   tis 1 or 2.

In certain embodiments, the compound is a compound of Formula I.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula I-A represented by:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and variables Z, R^(I-1) throughR^(I-13), R¹, R², and R³ are as defined for Formula I.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula I-A.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula I-B represented by:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and variables Z, R^(I-1) throughR^(I-13), R¹, R², and R³ are as defined for Formula I.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula I-B.

In more specific embodiments, deuterium-enriched compounds of the aboveFormulae (e.g., Formula I, I-A, and I-B) may be further characterizedaccording to the definition of R¹, wherein in certain embodiments, R¹ isone of the following:

wherein any H in R¹ is optionally replaced with D.

In certain embodiments, R¹ is one of the following:

In more specific embodiments, deuterium-enriched compounds describedherein may be further characterized according to the definition of R²and R³, wherein in certain embodiments, R² and R³ are fluoro.

In more specific embodiments, deuterium-enriched compounds describedherein may be further characterized according to the definition ofR^(I-1) through R^(I-3). In certain embodiments, R^(I-1) and R^(I-13)are H. In certain embodiments, R^(I-2), R^(I-3), R^(I-4), and R^(I-5)are H. In certain embodiments, R^(I-6), R^(I-7), R^(I-8), R^(I-9), andR^(I-10) are H. In certain embodiments, R^(I-11) and R^(I-12) are H.

Another aspect of the invention provides a deuterium-enriched compoundof Formula II:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is H or D, provided that the abundance of deuterium in Z is at        least 30%;    -   R^(I-1), R^(I-2), R^(I-3), R^(I-4), R^(I-5), R^(I-6), R^(I-7),        R^(I-8), R^(I-9), R^(I-10), R^(I-11), R^(I-12), and R^(I-13) are        independently H or D;    -   Q¹ represents independently for each occurrence alkyl, halogen,        haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted        cycloalkyl, optionally substituted cycloalkylalkyl, optionally        substituted aryl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷)        or R⁴OR⁴C(J)N(R⁶)(R⁷);    -   J is O or S;    -   R⁴ represents independently for each occurrence alkylene,        alkenylene or a direct bond;    -   R⁵ represents independently for each occurrence hydrogen, alkyl,        halo, alkoxy, haloalkyl or hydroxyalkyl;    -   R⁶ and R⁷ are selected as follows:        -   i) R⁶ and R⁷ are each independently hydrogen or alkyl; or        -   ii) R⁶ and R⁷ are together with the nitrogen atom on which            they are attached to form a 5 or 6-membered heterocyclyl or            heteroaryl ring, optionally substituted with one or two            halo, alkyl or haloalkyl; and    -   n is 0, 1, 2, or 3.

Deuterium-enriched compounds described herein (e.g., Formula I, I-A,I-B, and II) may be further characterized according to the extent ofdeuterium enrichment at the position defined by variable Z and/or thestereochemical purity of the compound at the position defined byvariable Z. For example, in certain embodiments, the abundance ofdeuterium in Z is at least 60%. In certain other embodiments, theabundance of deuterium in Z is at least 75%. In yet other embodiments,the abundance of deuterium in Z is at least 90%. In yet otherembodiments, the abundance of deuterium in Z is at least 95%. In yetother embodiments, the abundance of deuterium in Z is from about 80% toabout 99%, about 85% to about 99%, or about 90% to about 99%. In yetother embodiments, the abundance of deuterium in Z is selected from: (a)at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e)at least 75%, (f) at least 80%, (g) at least 90%, (h) at least 95%, (i)at least 97%, and (j) about 100%. Additional examples of the abundanceof deuterium in Z include about 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99 to about 100%.

In certain embodiments, the compound has a stereochemical purity of atleast 85% enantiomeric excess at the carbon atom bearing variable Z. Incertain other embodiments, the compound has a stereochemical purity ofat least 90% enantiomeric excess at the carbon atom bearing variable Z.In certain other embodiments, the compound has a stereochemical purityof at least 95% enantiomeric excess at the carbon atom bearing variableZ. In certain other embodiments, the compound has a stereochemicalpurity of at least 98% enantiomeric excess at the carbon atom bearingvariable Z. In certain other embodiments, the compound has astereochemical purity of at least 99% enantiomeric excess at the carbonatom bearing variable Z. In other embodiments, the deuterium-enrichedcompound has a stereochemical purity of at least 80%, 85%, 90%, 95%, or98% enantiomeric excess at a chiral carbon atom bearing variable Z, andyet additional examples of stereochemical purity include an enantiomericexcess of at least 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% at achiral carbon atom bearing variable Z.

In yet other embodiments, the deuterium-enriched compound may containstereogenic centers in addition to the stereogenic center at the carbonatom bearing variable Z, and such deuterium-enriched compounds may beprovided in stereochemically pure form, such as where the compound hasan overall stereochemical purity of at least 90%, 95%, 98% or 99%, whichmay be expressed as a diastereomeric excess of at least 90%, 95%, 98% or99%.

In yet other embodiments, the compound is a compound in Table 1 or apharmaceutically acceptable salt thereof.

No. Chemical Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

In yet other embodiments, the compound is a compound in Table 2 or apharmaceutically acceptable salt thereof.

TABLE 2 No. Chemical Structure 1

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 2

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 3

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 4

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 5

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 6

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 7

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 8

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 9

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 10

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 11

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 12

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 13

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 14

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 15

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 16

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 17

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 18

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 19

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 20

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 21

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 22

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 23

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 24

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 25

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 26

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 27

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 28

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 29

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 30

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 31

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 32

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 33

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 34

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 35

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 36

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D.

In certain embodiments, compounds in Table 2 may be furthercharacterized by a high stereochemical purity, such as where thecompound has a stereochemical purity of at least 85% enantiomeric excessat the carbon atom bearing D. In certain embodiments, the compound has astereochemical purity of at least 90% enantiomeric excess at the carbonatom bearing D. In certain embodiments, the compound has astereochemical purity of at least 95% enantiomeric excess at the carbonatom bearing D. In certain embodiments, the compound has astereochemical purity of at least 98% enantiomeric excess at the carbonatom bearing D.

In another aspect, the invention provides a deuterium-enriched compoundthat is a compound from Table 3 or a pharmaceutically acceptable saltthereof, having (i) at least 30 mole % deuterium at the stereogeniccenter of the 2,6-dioxopiperidin-3-yl group of said compound, and (ii)optionally at least 30 mole % deuterium at one or more hydrogenpositions of the compound recited in the following table.

TABLE 3 No. Chemical Name  1N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide  22-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  3N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide  4N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(p-tolyl)acetamide  52-(3,4-dichiorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  62-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  72-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  8N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide  92-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  10N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide  112-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  122-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  132-(5-chloro-2-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  14N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoro-2-methoxyphenyl)acetamide  15N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(o-tolyl)acetamide  162-(4-(2-(dimethylamino)-2-oxoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 17 2-(2,5-dimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  18N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide  19N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide  20N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide  212-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  22N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoropropanamide  23N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2,3,3-tetrafluoropropanamide  24N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluorobutanamide  25N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-3-hydroxy-3-methylbutanamide  262-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  27N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide  282-(3-chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  29N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(m-tolyl)acetamide  30N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide  312-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  32N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide  33N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide  34N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide  352-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  36N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide  372-(4-cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  382-(4-chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  392-(4-chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  40N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide  412-(3-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  42N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide  432-(4-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  44N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide  452-(4-chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  462-cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  472-(4-chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  48N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide  49N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide  50N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetamide  51N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide  522-(3-(dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  53N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide  54N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide  55N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide  56N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide  57N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide  58N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide  59N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide  60N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide  61N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide  62N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide  63N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide  64N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide  652-(3-chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  66N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide  67N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide  682-(5-chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  69N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide  702-(2,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  712-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  72N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide  73N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(l-hydroxycyclohexyl)acetamide  74N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(l-hydroxycyclopentyl)acetamide  75N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide  76N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide  77N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide  78N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide  79N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetamide  80N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4'-fluorobiphenyl-4-yl)acetamide  81N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide  822-cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  83N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide  84N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide  85N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide  862-(4-chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide  87N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide  88N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide  89N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide  90N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide  91N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide  92N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide  93N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide  94N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide  95N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide  962-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide hydrochloride  97N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide  98N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide  99N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide 100N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide 1012-(l-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide102 N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide 103N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(l-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide 1042-(5-tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 1052-(5-cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 106N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide 1072-(5-bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 108N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide 109N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide 110N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide 111N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide 1122-(2-aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 113N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetamide 114N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylamino)ethoxy)phenyl)acetamide hydrochloride 115N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(l-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide 1162-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 117N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide 118N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide 119N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetamide 1202-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide121 N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(l-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide 122N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetamide

In certain embodiments, the compound is a compound in Table 3 whereinthe only site of deuterium-enrichment in the compound is at thestereogenic center of the 2,6-dioxopiperidin-3-yl group of saidcompound. In certain embodiments, deuterium-enrichment at thestereogenic center of the 2,6-dioxopiperidin-3-yl group is at least 80mole percent. In certain embodiments, deuterium-enrichment at thestereogenic center of the 2,6-dioxopiperidin-3-yl group is at least 90mole percent. In certain embodiments, deuterium-enrichment at thestereogenic center of the 2,6-dioxopiperidin-3-yl group is at least 95mole percent. In certain embodiments, deuterium-enrichment at thestereogenic center of the 2,6-dioxopiperidin-3-yl group is at least 98mole percent. In certain embodiments, the deuterium-enriched compound isfurther characterized according to stereochemical features andstereochemical purity, such as where the compound has theR-configuration at the stereogenic center of the 2,6-dioxopiperidin-3-ylgroup, and the compound has a stereochemical purity of at least 75% atthe stereogenic center of the 2,6-dioxopiperidin-3-yl group. In certainother embodiments, the deuterium-enriched compound is characterized byone of the following: (i) it has the R-configuration at the stereogeniccenter of the 2,6-dioxopiperidin-3-yl group, and the compound has astereochemical purity of at least 90% at the stereogenic center of the2,6-dioxopiperidin-3-yl group; (ii) it has the R-configuration at thestereogenic center of the 2,6-dioxopiperidin-3-yl group, and thecompound has a stereochemical purity of at least 95% at the stereogeniccenter of the 2,6-dioxopiperidin-3-yl group; (iii) has theS-configuration at the stereogenic center of the 2,6-dioxopiperidin-3-ylgroup, and the compound has a stereochemical purity of at least 75% atthe stereogenic center of the 2,6-dioxopiperidin-3-yl group; (iv) it hasthe S-configuration at the stereogenic center of the2,6-dioxopiperidin-3-yl group, and the compound has a stereochemicalpurity of at least 90% at the stereogenic center of the2,6-dioxopiperidin-3-yl group; or (v) it has the S-configuration at thestereogenic center of the 2,6-dioxopiperidin-3-yl group, and thecompound has a stereochemical purity of at least 95% at the stereogeniccenter of the 2,6-dioxopiperidin-3-yl group.

Another aspect of the invention provides compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein any hydrogen atomis optionally replaced with D.

In certain embodiments, compound is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, compound is a compound in the table below or apharmaceutically acceptable salt thereof:

No. Chemical Structure 1

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D. 2

  having a stereochemical purity of at least 75% enantiomeric excess atthe carbon atom bearing D.In certain embodiments, compounds in the foregoing table may be furthercharacterized by a high stereochemical purity, such as where thecompound has a stereochemical purity of at least 85% enantiomeric excessat the carbon atom bearing D. In certain embodiments, the compound has astereochemical purity of at least 90% enantiomeric excess at the carbonatom bearing D. In certain embodiments, the compound has astereochemical purity of at least 95% enantiomeric excess at the carbonatom bearing D. In certain embodiments, the compound has astereochemical purity of at least 98% enantiomeric excess at the carbonatom bearing D.

In another aspect, the invention provides a deuterium-enriched form of acompound described in WO 2016/007848, which is hereby incorporated byreference. The deuterium enriched compound has at least 30% deuteriumenrichment at any stereogenic center containing a hydrogen atom in thecompound in WO 2016/007848. In certain embodiments, the deuteriumenriched compound optionally contains one or more additional sites ofdeuterium enrichment in addition to the aforementioned deuteriumenrichment at the stereogenic center containing a hydrogen atom in thecompound in WO 2016/007848.

In another aspect, the invention provides a pharmaceutical compositioncomprising a deuterium-enriched compound described herein and apharmaceutically acceptable carrier.

Deuterium-enriched compounds of the invention can generally be preparedby substituting a deuterium-enriched reagent for a non-isotopicallylabeled reagent in synthetic schemes reported in the literature formaking non-isotopically labeled piperidinonyl-oxoisoindolinyl acetamidecompounds. One publication describing methods for preparingnon-isotopically labeled compounds of these types, and which alsodescribe compounds that may be used in the present invention, includes,for example, WO 2016/007848, which is hereby incorporated by reference.

Schemes 1 and 2 below illustrates a general method for preparingdeuterium-enriched piperidinonyl-oxoisoindolinyl acetamide compoundsenriched with deuterium at one or more positions. The scheme anddescription below are provided for the purpose of illustrating theinvention, and should not be regarded in any manner as limiting thescope or the spirit of the invention.

As shown in Scheme 1, the preparation of a deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compound may begin by reactingdeuterium-enriched 3-aminopiperidine-2,6-dione A with benzoate ester Bto form intermediate C. Intermediate C may be converted to amine D usingprocedures set forth in WO 2016/007848. Amide coupling may be used toconvert amine D to amide E having the desired R¹ group, such as anoptionally substituted phenyl.

Compounds having deuterium enrichment at a position other than thosespecifically mentioned above can be prepared by selecting an appropriatedeuterium-enriched starting material, or by known methods of introducinga deuterium atom or exchanging a proton for a deuteron that are known inthe art.

As an alternative synthetic procedure, a deuterium-enrichedpiperidinonyl-oxoisoindolinyl acetamide compound may be prepared bysubjecting a compound to deuterium/hydrogen exchange, such as subjectingthe compound to D₂O/base conditions followed by usual workup andisolation of the deuterated material, as illustrated in Scheme 2.

Deuterium-enriched compounds (e.g., compound E) may be used in racemicform or they may be synthesized in enantioenriched form, e.g., byemploying A in enantioenriched form. Enantioenriched form of deuteratedcompounds may also be achieved by separating the R-enantiomer andS-enantiomer using chiral chromatography, such as chiralhigh-performance liquid chromatography. Alternatively, the R-enantiomerand S-enantiomer of E may be separated by reaction with a chiralcarboxylic acid to form a salt, followed by separation of the resultingdiastereomeric salts, and conversion of the separated salts back to thedeuterated free base in enantiopure form.

Compounds described herein can be provided in isolated or purified form.Isolated or purified compounds are a group of compounds that have beenseparated from their environment, such as from a crude reaction mixtureif made in a laboratory setting or removed from their naturalenvironment if naturally occurring. Examples of the purity of theisolated compound include, for example, at least 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, to 100% by weight.

Another aspect of the invention provides a unit quantum of adeuterium-enriched compound described herein, such as an amount of atleast (a) one μg of a disclosed deuterium-enriched compound, (b) one mg,or (c) one gram. In further embodiments, the quantum is, for example, atleast 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, or 1 moleof the compound. The present amounts also cover lab-scale (e.g., gramscale including 1, 2, 3, 4, 5 g, etc.), kilo-lab scale (e.g., kilogramscale including 1, 2, 3, 4, 5 kg, etc.), and industrial or commercialscale (e.g., multi-kilogram or above scale including 100, 200, 300, 400,500 kg, etc.) quantities as these will be more useful in the actualmanufacture of a pharmaceutical. Industrial/commercial scale refers tothe amount of product that would be produced in a batch that wasdesigned for clinical testing, formulation, sale/distribution to thepublic, etc.

II. Therapeutic Applications

The invention provides methods of using deuterium-enriched compoundsdescribed herein to treat medical disorders. The deuterium-enrichedcompound can be, for example, a compound of Formula I, I-A, I-B, or II,or one of the other deuterium-enriched compounds described in Section Iabove. Various aspects of the invention pertaining to treating medicaldisorders are described below.

Accordingly, one aspect of the invention provides a method of treating amedical disorder in a patient. The method comprises administering to apatient in need thereof a therapeutically effective amount of a compounddescribed herein, such as a deuterium-enriched compound described inSection 1 above, to treat the disorder. The disorder may be, forexample, selected from the group consisting of cancer, an immunedisorder, and an inflammatory disorder. In certain embodiments, thedisorder is cancer (e.g., a cancer of the bladder, bone, blood, brain,breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney,liver, lymph node, lung, mouth, neck, ovary, pancreas, prostate, rectum,stomach, testis, throat, or uterus.)

Without being limited by a particular theory, compounds provided hereinare expected to control angiogenesis or inhibit the production ofcertain cytokines. Further, compounds provided herein may beimmunomodulatory and/or cytotoxic, and thus, may be useful aschemotherapeutic agents. Consequently, without being limited by aparticular theory, some or all of such characteristics possessed by thecompounds provided herein may render them useful in treating variousdiseases or disorders. For example, enhanced or unregulated angiogenesishas been implicated in a number of diseases and medical conditionsincluding, but not limited to, ocular neovascular diseases, choroidalneovascular diseases, retina neovascular diseases, rubeosis iridis(neovascularization of the angle of the eye), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, fibrosis, arthritisand autoimmune diseases. Further examples of such diseases andconditions include, but are not limited to: diabetic retinopathy;retinopathy of prematurity; corneal graft rejection; neovascularglaucoma; retrolental fibroplasia; and proliferative vitreoretinopathy.

Still further exemplary diseases or disorders include, but are notlimited to, cancer, disorders associated with angiogenesis, painincluding, but not limited to, Complex Regional Pain Syndrome (“CRPS”),Macular Degeneration (“MD”) and related syndromes, skin diseases,pulmonary disorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders (including tauopathies), CNSinjury, atherosclerosis and related disorders, dysfunctional sleep andrelated disorders, hemoglobinopathy and related disorders (e.g.,anemia), TNF-α related disorders, amyloidoses, and other variousdiseases and disorders.

Examples of cancer and precancerous conditions that may be treated bythe present methods include, but are not limited to, those described ininternational patent application WO 2016/007848, in U.S. Pat. Nos.6,281,230 and 5,635,517 to Muller et al., in various U.S. patentpublications to Zeldis, including U.S. Patent Publication Nos.2004/0220144A1, published Nov. 4, 2004 (Treatment of MyelodysplasticSyndrome); 2004/0029832A1, published Feb. 12, 2004 (Treatment of VariousTypes of Cancer); and 2004/0087546, published May 6, 2004 (Treatment ofMyeloproliferative Diseases). Examples also include those described inWO 2004/103274, published Dec. 2, 2004. All of these references areincorporated herein in their entireties by reference.

Specific examples of cancer that may be treated by the present methodsinclude, but are not limited to, cancers of the skin, such as melanoma;lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary;prostate; colon; rectum; mouth; brain; head and neck; throat; testes;kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages;and AIDS-related cancers. The compounds are also useful for treatingcancers of the blood and bone marrow, such as multiple myeloma and acuteand chronic leukemias, for example, lymphoblastic, myelogenous,lymphocytic, and myelocytic leukemias. The compounds provided herein canbe used for treating, preventing or managing either primary ormetastatic tumors.

Other specific cancers that may be treated by the present methodinclude, but are not limited to, advanced malignancy, amyloidosis,neuroblastoma, meningioma, hemangiopericytoma, multiple brainmetastases, glioblastoma multiforme, glioblastoma, brain stem glioma,poor prognosis malignant brain tumor, malignant glioma, recurrentmalignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,neuroendocrine tumor, rectal adenocarcinoma, Dukes C colorectal cancer,Dukes D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, acute myeloblastic leukemia,chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuselarge B-cell lymphoma, low grade follicular lymphoma, metastaticmelanoma (localized melanoma, including, but not limited to, ocularmelanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressiva, hormone-refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen-independentprostate cancer, androgen-dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another aspect, the cancer isrefractory or resistant to chemotherapy or radiation.

Accordingly, in certain embodiments, the cancer is an advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes Ccolorectal cancer, Dukes D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acutemyeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse largeB-Cell lymphoma, low grade follicular lymphoma, malignant melanoma,malignant mesothelioma, malignant pleural effusion mesotheliomasyndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologicsarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressiva, hormone-refractory prostate cancer, resected high-risk softtissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen-independent prostate cancer, androgen-dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.In certain other embodiments, the cancer is a cancer of the bladder,bone, blood, brain, breast, cervix, chest, colon, endometrium,esophagus, eye, head, kidney, liver, lymph node, lung, mouth, neck,ovary, pancreas, prostate, rectum, stomach, testis, throat, or uterus.

In certain embodiments, the cancer is a solid tumor or a blood-bornetumor. The solid tumor and/or blood-borne tumor may be metastatic and/ordrug resistant. In certain embodiments, the cancer is myeloma orlymphoma. In certain embodiments, the solid tumor is a hepatocellularcarcinoma, glioblastoma, prostate cancer, colorectal cancer, ovariancancer, or renal cancer.

In certain embodiments, the cancer is a non-Hodgkin's lymphoma that is adiffuse large B-cell lymphoma (such as characterized as being anactivated B-cell phenotype). In yet other embodiments, the cancer is anon-Hodgkin's lymphoma that is a diffuse large B-cell lymphomacharacterized by the expression of one or more biomarkers overexpressedin RIVA, U2932, TMD8, or OCI-Ly10 cell lines.

In certain embodiments, the cancer is relapsed or refractory.

In another aspect, provided herein are methods of treating various formsof leukemias such as chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia andacute myeloblastic leukemia, including leukemias that are relapsed,refractory or resistant, as disclosed in U.S. Patent Publication No.2006/0030594, published Feb. 9, 2006, which is incorporated in itsentirety by reference. Accordingly, in certain embodiments, the cancerto be treated is leukemia, such as chronic lymphocytic leukemia, chronicmyelocytic leukemia, acute lymphoblastic leukemia, or acute myeloidleukemia.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another aspect, provided herein are methods of treating various typesof lymphomas, including Non-Hodgkin's lymphoma (NHL). The term“lymphoma” refers to a heterogeneous group of neoplasms arising in thereticuloendothelial and lymphatic systems. “NHL” refers to malignantmonoclonal proliferation of lymphoid cells in sites of the immunesystem, including lymph nodes, bone marrow, spleen, liver andgastrointestinal tract. Examples of NHL include, but are not limited to,mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediatedifferentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorlydifferentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffusesmall-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any typeof the mantle cell lymphomas that can be seen under the microscope(nodular, diffuse, blastic and mantle zone lymphoma).

Additional exemplary diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, inflammatory diseases, autoimmune diseases, viral diseases, geneticdiseases, allergic diseases, bacterial diseases, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,and rubeosis iridis (neovascularization of the angle of the eye).Specific examples of the diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, arthritis, endometriosis, Crohn's disease, heart failure, advancedheart failure, renal impairment, endotoxemia, toxic shock syndrome,osteoarthritis, retrovirus replication, wasting, meningitis,silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder,malignancy-associated hypercalcemia, stroke, circulatory shock,periodontitis, gingivitis, macrocytic anemia, refractory anemia, and5q-deletion syndrome.

In certain embodiments, the disorder to be treated is an immune diseaseor an inflammatory disease. In certain other embodiments, the disorderto be treated is systemic lupus erythematosus, scleroderma, Sjogren'ssyndrome, ANCA-induced vasculitis, anti-phospholipid syndrome, ormyasthenia gravis. The scleroderma may be localized, systemic, limited,or diffuse scleroderma. In certain embodiments, the systemic sclerodermacomprises CREST syndrome (calcinosis, Raynaud's syndrome, esophagealdysfunction or dysmotility, sclerodactyly, telangiectasia). Sclerodermais also known as systemic sclerosis or progressive systemic sclerosis.In certain embodiments, systemic sclerosis comprises scleroderma lungdisease, scleroderma renal crisis, cardiac manifestations, muscularweakness (including fatigue or limited CREST), gastrointestinaldysmotility and spasm, and abnormalities in the central, peripheral andautonomic nervous system (including carpal tunnel syndrome followed bytrigeminal neuralgia). It also includes general disability, includingdepression, and impact on quality of life. In certain embodiments,limited scleroderma is limited to the hands, the face, neck, orcombinations thereof. In certain embodiments, diffuse sclerodermacomprises skin tightening and also occurs above the wrists (or elbows).In yet other embodiments, diffuse systemic sclerosis is sinescleroderma, comprising internal organ fibrosis, but no skin tightening;or familial progressive systemic sclerosis.

In certain embodiments, the disorder to be treated is Raynaud's diseaseor syndrome.

Another aspect of the invention provides a method for treating a symptomof systemic lupus erythematosus by administering to a patient sufferingfrom systemic lupus erythematosus a deuterium-enriched compounddescribed herein, wherein the symptom is one or more of joint pain,joint swelling, arthritis, chest pain when taking a deep breath,fatigue, fever with no other cause, general discomfort, uneasiness, hairloss, mouth sores, swollen lymph nodes, sensitivity to sunlight, skinrash, headaches, numbness, tingling, seizures, vision problems,personality changes, abdominal pain, nausea, vomiting, abnormal heartrhythms, coughing up blood, difficulty breathing, patchy skin color, orRaynaud's phenomenon.

Another aspect of the invention provides a method for treating a symptomof scleroderma by administering to a patient suffering from sclerodermaa deuterium-enriched compound described herein, wherein the symptom isone or more of (i) gradual hardening, thickening, and tightening of theskin; (ii) skin discoloration; (iii) numbness of extremities; (iv) shinyskin; (v) small white lumps under the surface of the skin that eruptinto a chalky white fluid; (vi) Raynaud's esophageal dysfunction; (vii)telangiectasia; (viii) pain and/or stiffness of the joints; (ix)swelling of the hands and feet; (x) itching of the skin; (xi) stiffeningand curling of the fingers; (xii) ulcers on the outside of certainjoints, such as knuckles and elbows; (xiii) digestive problems, such asheartburn, difficulty swallowing, diarrhea, irritable bowel, andconstipation; (xiv) fatigue and weakness; (xv) shortness of breath;(xvi) arthritis; (xvii) hair loss; (xviii) internal organ problems;(xix) digital ulcers; and (xx) digital auto-amputation.

Another aspect of the invention provides a method for improving themodified Rodnan skin score, reducing or improving the skin thickness,reducing or improving skin induration, improving the pulmonary function,improving the dermatology quality of life index, improving the carbonmonoxide diffusing capacity, improving the Mahler Dyspnea index,improving the Saint George's Respiratory Questionnaire score, improvingthe UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tractscore, improving flow-mediated dilatation, or improving or increasingthe six minute walk distance of a patient having scleroderma, comprisingadministering to the patient an effective amount of a deuterium-enrichedcompound described herein.

Another aspect of the invention provides a method for modulatingactivity of a cell selected from the group consisting of a B cell and aT cell, comprising contacting the cell with an effective amount of adeuterium-enriched compound described herein to modulate the activity ofthe cell.

Another aspect of the invention provides a method for treating animmune-related disorder or a disorder selected from the group consistingof ANCA-induced vasculitis, myasthenia gravis, Addison's disease,alopecia areata, ankylosing spondylitis, antiphospholipid-antibodysyndrome, antiphospholipid syndrome (primary or secondary), asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner-ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatricialpemphigoid (e.g., mucous membrane pemphigoid), cold agglutinin disease,Degos disease, dermatitis hepatiformis, essential mixedcryoglobulinemia, Goodpasture's syndrome, Graves' disease,Guillain-Barre syndrome, Hashimoto's thyroiditis (Hashimoto's disease;autoimmune thyroiditis), idiopathic pulmonary fibrosis, idiopathicthrombocytopenia purpura, IgA nephropathy, juvenile arthritis, lichenplanus, Meniere's disease, mixed connective-tissue disease, morphea,narcolepsy, neuromyotonia, pediatric autoimmune neuropsychiatricdisorders associated with streptococcal infection (PANDAs), pemphigusvulgaris, pernicious anemia, polyarteritis nodosa, polychondritis,polymyalgia rheumatica, primary agammaglobulinemia, primary biliarycirrhosis, Raynaud's disease (Raynaud's phenomenon), Reiter's syndrome,relapsing polychondritis, rheumatic fever, Sjogren's syndrome,stiff-person syndrome (Moersch-Woltmann syndrome), Takayasu's arteritis,temporal arteritis (giant cell arteritis), uveitis, vasculitis (e.g.,vasculitis not associated with lupus erythematosus), vitiligo, andWegener's granulomatosis. The method comprises administering to apatient in need thereof a therapeutically effective amount of adeuterium-enriched compound described herein to treat the disorder.

Another aspect of the invention provides a method of treating pain in asubject, comprising administering to a patient in need thereof atherapeutically effective amount of a deuterium-enriched compounddescribed herein. Exemplary types of pain include nociceptive pain,neuropathic pain, mixed pain of nociceptive and neuropathic origin,visceral pain, migraine, headache, and post-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, complexregional pain syndrome (CRPS) type I, CRPS type II, reflex sympatheticdystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy,sympathetically maintained pain syndrome, causalgia, Sudeck's atrophy ofbone, algoneurodystrophy, shoulder hand syndrome, post-traumaticdystrophy, trigeminal neuralgia, post-herpetic neuralgia, cancer-relatedpain, phantom-limb pain, fibromyalgia, chronic fatigue syndrome, spinalcord injury pain, central post-stroke pain, radiculopathy, diabeticneuropathy, post-stroke pain, luetic neuropathy, and other painfulneuropathic conditions such as those induced by drugs such asvincristine and bortezomib.

Complex regional pain syndrome (CRPS) and CRPS and related syndromesmean a chronic pain disorder characterized by one or more of thefollowing: pain, whether spontaneous or evoked, including allodynia(painful response to a stimulus that is not usually painful) andhyperalgesia (exaggerated response to a stimulus that is usually onlymildly painful); pain that is disproportionate to the inciting event(e.g., years of severe pain after an ankle sprain); regional pain thatis not limited to a single peripheral nerve distribution; and autonomicdysregulation (e.g., edema, alteration in blood flow and hyperhidrosis)associated with trophic skin changes (hair and nail growth abnormalitiesand cutaneous ulceration).

Further types of pain contemplated for treatment include, but are notlimited to, those described in U.S. Patent Publication No. 2005/0203142,published Sep. 15, 2005, which is incorporated in its entirety herein byreference.

Examples of macular degeneration (MD) and related syndromes include, butare not limited to, those described in U.S. Patent Publication No.2004/0091455, published May 13, 2004, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, atrophic (dry) MD, exudative (wet) MD, age-relatedmaculopathy (ARM), choroidal neovascularisation (CNV), retinal pigmentepithelium detachment (PED), and atrophy of retinal pigment epithelium(RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0214328A1, published Sep.29, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, keratoses and relatedsymptoms, skin diseases or disorders characterized with overgrowths ofthe epidermis, acne, and wrinkles.

“Keratosis” refers to any lesion on the epidermis marked by the presenceof circumscribed overgrowths of the horny layer, including but notlimited to, actinic keratosis, seborrheic keratosis, keratoacanthoma,keratosis follicularis (Darier's disease), inverted follicularkeratosis, palmoplantar keratoderma (PPK, keratosis palmaris etplantaris), keratosis pilaris, and stucco keratosis. The term “actinickeratosis” also refers to senile keratosis, keratosis senilis, verrucasenilis, plana senilis, solar keratosis, keratoderma or keratoma. Theterm “seborrheic keratosis” also refers to seborrheic wart, senile wart,or basal cell papilloma. Keratosis is characterized by one or more ofthe following symptoms: rough appearing, scaly, erythematous papules,plaques, spicules or nodules on exposed surfaces (e.g., face, hands,ears, neck, legs and thorax), excrescences of keratin referred to ascutaneous horns, hyperkeratosis, telangiectasia, elastosis, pigmentedlentigines, acanthosis, parakeratosis, dyskeratosis, papillomatosis,hyperpigmentation of the basal cells, cellular atypia, mitotic figures,abnormal cell-cell adhesion, dense inflammatory infiltrates and smallprevalence of squamous cell carcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratosis, sign of Leser-Trelat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, Cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0239842A1, published Oct.27, 2005, which is incorporated in its entirety herein by reference.Specific examples include pulmonary hypertension and related disorders.Examples of pulmonary hypertension and related disorders include, butare not limited to: primary pulmonary hypertension (PPH); secondarypulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillarypulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonaryartery hypertension; idiopathic pulmonary hypertension; thromboticpulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy;functional classes I to IV pulmonary hypertension; and pulmonaryhypertension associated with, related to, or secondary to, leftventricular dysfunction, mitral valvular disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis,anomalous pulmonary venous drainage, pulmonary venoocclusive disease,collagen vascular disease, congenital heart disease, HIV virusinfection, drugs and toxins such as fenfluramine, congenital heartdisease, pulmonary venous hypertension, chronic obstructive pulmonarydisease (COPD), interstitial lung disease, sleep-disordered breathing,alveolar hypoventilation disorder, chronic exposure to high altitude,neonatal lung disease, alveolar-capillary dysplasia, sickle celldisease, other coagulation disorders, chronic thromboemboli, connectivetissue disease, lupus including systemic and cutaneous lupus,schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but are not limited to,those described in U.S. Patent Publication No. 2005/0100529, publishedMay 12, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, mesothelioma,asbestosis, malignant pleural effusion, benign exudative effusion,pleural plaques, pleural calcification, diffuse pleural thickening,rounded atelectasis, fibrotic masses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2006/0154880, published Jul.13, 2006, which is incorporated in its entirety herein by reference.Parasitic diseases include diseases and disorders caused by humanintracellular parasites such as, but not limited to, P. falciparum, P.ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica,L. major, L. tropica, L. mexicana, L. braziliensis, T. Gondii, B.microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E.histolytica, I. belli, S. mansonii, S. haematobium, Trypanosoma spp.,Toxoplasma spp., and O. volvulus. Other diseases and disorders caused bynon-human intracellular parasites such as, but not limited to, Babesiabovis, Babesia canis, Banesia gibsoni, Besnoitia darlingi, Cytauxzoonfelis, Eimeria spp., Hammondia spp., and Theileria spp., are alsoencompassed. Specific examples include, but are not limited to, malaria,babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis,meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. patent application Ser. No. 11/289,723, filedNov. 30, 2005. Specific examples include, but are not limited to,adenosine deaminase deficiency, antibody deficiency with normal orelevated Igs, ataxia-telangiectasia, bare lymphocyte syndrome, commonvariable immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0143344, published Jun.30, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, amyotrophic lateralsclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington'sdisease, multiple sclerosis, other neuroimmunological disorders such asTourette syndrome, delirium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. Patent Publication No. 2006/0122228,published Jun. 8, 2006, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, CNSinjury/damage and related syndromes, including, but not limited to,primary brain injury, secondary brain injury, traumatic brain injury,focal brain injury, diffuse axonal injury, head injury, concussion,post-concussion syndrome, cerebral contusion and laceration, subduralhematoma, epidermal hematoma, post-traumatic epilepsy, chronicvegetative state, complete spinal cord injury (SCI), incomplete SCI,acute SCI, subacute SCI, chronic SCI, central cord syndrome,Brown-Sequard syndrome, anterior cord syndrome, conus medullarissyndrome, cauda equina syndrome, neurogenic shock, spinal shock, alteredlevel of consciousness, headache, nausea, emesis, memory loss,dizziness, diplopia, blurred vision, emotional lability, sleepdisturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other diseases or disorders include, but are not limited to, viral,genetic, allergic, and autoimmune diseases. Specific examples include,but are not limited to, HIV, hepatitis, adult respiratory distresssyndrome, bone resorption diseases, chronic pulmonary inflammatorydiseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxicshock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusioninjury, meningitis, psoriasis, fibrotic disease, cachexia, graft versushost disease, graft rejection, auto-immune disease, rheumatoidspondylitis, Crohn's disease, ulcerative colitis, inflammatory boweldisease, multiple sclerosis, systemic lupus erythematosus, erythemanodosum leprosum (ENL) in leprosy, radiation damage, cancer, asthma, orhyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. Patent Publication No. 2002/0054899,published May 9, 2002, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, all formsof conditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary bypass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts.

Exemplary major systemic arteries that may be in need of treatment,include, for example, Axillary, Brachial, Brachiocephalic, Celiac,Common carotid, Common iliac, Coronary, Deep femoral, Digital, Dorsalispedis, External carotid, External iliac, Femoral, Gastric, Hepatic,Inferior mesenteric, Internal carotid, Internal iliac, Left gastric,Middle sacral, Ovarian, Palmar arch, Peroneal, Popliteal, Posteriortibial, Pulmonary, Radial, Renal, Splenic, Subclavian, Superiormesenteric, Testicular, and Ulnar.

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. Patent Publication No.2005/0222209A1, published Oct. 6, 2005, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, snoring, sleep apnea, insomnia, narcolepsy, restless legsyndrome, sleep terrors, sleep walking, sleep eating, and dysfunctionalsleep associated with chronic neurological or inflammatory conditions.Chronic neurological or inflammatory conditions, include, but are notlimited to, complex regional pain syndrome (CRPS), chronic low backpain, musculoskeletal pain, arthritis, radiculopathy, pain associatedwith cancer, fibromyalgia, chronic fatigue syndrome, visceral pain,bladder pain, chronic pancreatitis, neuropathies (diabetic,post-herpetic, traumatic or inflammatory), and neurodegenerativedisorders such as Parkinson's disease, Alzheimer's disease, amyotrophiclateral sclerosis (ALS), multiple sclerosis, Huntington's disease,bradykinesia, muscle rigidity, parkinsonian tremor, parkinsonian gait,motion freezing, depression, defective long-term memory,Rubinstein-Taybi syndrome (RTS), dementia, postural instability,hypokinetic disorders, synuclein disorders, multiple system atrophies,striatonigral degeneration, olivopontocerebellar atrophy, Shy-Dragersyndrome, motor neuron disease with parkinsonian features, Lewy bodydementia, Tau pathology disorders, progressive supranuclear palsy,corticobasal degeneration, frontotemporal dementia, amyloid pathologydisorders, mild cognitive impairment, Alzheimer's disease withparkinsonism, Wilson disease, Hallervorden-Spatz disease,Chediak-Higashi disease, SCA-3 spinocerebellar ataxia, X-linked dystoniaparkinsonism, prion disease, hyperkinetic disorders, chorea, ballismus,dystonia tremors, CNS trauma, and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. Patent Publication No.2005/0143420A1, published Jun. 30, 2005, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, hemoglobinopathy, sickle cell anemia, and any otherdisorders related to the differentiation of CD34+ cells.

Examples of TNF-α related disorders include, but are not limited to,those described in WO 2014/004990, WO 98/03502, and WO 98/54170, all ofwhich are incorporated herein in their entireties by reference. Specificexamples include, but are not limited to: endotoxemia or toxic shocksyndrome; cachexia; adult respiratory distress syndrome; bone resorptiondiseases such as arthritis; hypercalcemia; graft versus host reaction;cerebral malaria; inflammation; tumor growth; chronic pulmonaryinflammatory diseases; reperfusion injury; myocardial infarction;stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIVinfection and AIDS; other disorders such as rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and otherarthritic conditions, septic shock, sepsis, endotoxic shock, graftversus host disease, wasting, ulcerative colitis, multiple sclerosis,systemic lupus erythematosus, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as endotoxic shock,hemodynamic shock and sepsis syndrome, post-ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, graft rejection, oncogenic or cancerousconditions, asthma, autoimmune disease, radiation damages, and hyperoxicalveolar injury; viral infections, such as those caused by the herpesviruses; viral conjunctivitis; or atopic dermatitis.

In other aspects, the use of compounds provided herein in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in U.S. PatentPublication No. 2007/0048327, which is incorporated herein in itsentirety by reference, is also encompassed. These embodiments alsorelate to the uses of compounds provided herein in combination withvaccines to treat or prevent cancer or infectious diseases, and othervarious uses of immunomodulatory compounds such as reduction ordesensitization of allergic reactions.

Additional medical disorders for treatment include those described ininternational patent application publication nos. WO 2012/125459 and WO2012/125475, each of which is hereby incorporated by reference.

In one aspect, the invention provides a method for treating a disorderselected from the group consisting of angiogenesis and acytokine-related disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a deuterium-enrichedcompound described herein to treat the disorder.

In one aspect, the invention provides a method of treating cancer in apatient, comprising administering to a patient in need thereof atherapeutically effective amount of a deuterium-enriched compounddescribed herein to treat the cancer.

In certain embodiments, the cancer is a cancer of the bladder, bone,blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye,head, kidney, liver, lymph node, lung, mouth, neck, ovary, pancreas,prostate, rectum, stomach, testis, throat, or uterus.

In certain embodiments, the cancer is an advanced malignancy,amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiplebrain metastases, glioblastoma multiforme, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes Ccolorectal cancer, Dukes D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acutemyeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse largeB-cell lymphoma, low grade follicular lymphoma, malignant melanoma,malignant mesothelioma, malignant pleural effusion mesotheliomasyndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologicsarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressiva, hormone refractory prostate cancer, resected high-risk softtissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen-independent prostate cancer, androgen-dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

In one aspect, the invention provides a method of treating a disorderselected from the group consisting of an immune disorder and aninflammatory disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a deuterium-enrichedcompound described herein to treat the disorder.

In certain embodiments, the disorder is Sjogren's syndrome, ANCA-inducedvasculitis, Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid antibody syndrome, antiphospholipid syndrome, asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatricialpemphigoid, cold agglutinin disease, Degos disease, dermatitishepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome,Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis,idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Meniere's disease, mixedconnective tissue disease, morphea, narcolepsy, neuromyotonia, apediatric autoimmune neuropsychiatric disorder, pemphigus vulgaris,pernicious anemia, polyarteritis nodosa, polychondritis, polymyalgiarheumatica, primary agammaglobulinemia, primary biliary cirrhosis,Raynaud's disease, Reiter's syndrome, relapsing polychondritis,rheumatic fever, stiff-person syndrome, Takayasu's arteritis, temporalarteritis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis.

In certain embodiments, the disorder is systemic lupus erythematosus,scleroderma, Sjogren's syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, or myasthenia gravis.

Additional disorders and methods of treatment are disclosed in U.S. Pat.No. 8,518,972, U.S. Patent Publication Nos. 2013/0324518 and2015/0119435, and international patent application publications WO2011/100380 and WO 2014/004990; all of which are hereby incorporated byreference in their entireties.

In one aspect, the present invention provides a method of treating adisorder selected from the group consisting of cancer, an immunedisorder, and an inflammatory disorder, comprising administering to apatient in need thereof a therapeutically effective amount of adeuterium-enriched compound described herein to treat the disorder.

In certain embodiments, the disorder is cancer. In certain embodiments,the cancer is a cancer of the bladder, bone, blood, brain, breast,cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver,lymph node, lung, mouth, neck, ovary, pancreas, prostate, rectum,stomach, testis, throat, or uterus. In certain embodiments, the canceris leukemia. In certain embodiments, the cancer is chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, oracute myeloid leukemia. In certain embodiments, the cancer is anadvanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastases, glioblastoma multiforme,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C colorectal cancer, Dukes D colorectal cancer,unresectable colorectal carcinoma, metastatic hepatocellular carcinoma,Kaposi's sarcoma, acute myeloblastic leukemia, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-celllymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma,malignant melanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressiva, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen-independentprostate cancer, androgen-dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, or leiomyoma.

In certain embodiments, the disorder is an immune disorder.

In certain embodiments, the disorder is an inflammatory disorder.

In certain embodiments, the disorder is Sjogren's syndrome, ANCA-inducedvasculitis, Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid antibody syndrome, antiphospholipid syndrome, asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatricialpemphigoid, cold agglutinin disease, Degos disease, dermatitishepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome,Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis,idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Meniere's disease, mixedconnective tissue disease, morphea, narcolepsy, neuromyotonia, apediatric autoimmune neuropsychiatric disorder, pemphigus vulgaris,pernicious anemia, polyarteritis nodosa, polychondritis, polymyalgiarheumatica, primary agammaglobulinemia, primary biliary cirrhosis,Raynaud's disease, Reiter's syndrome, relapsing polychondritis,rheumatic fever, stiff-person syndrome, Takayasu's arteritis, temporalarteritis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis.

In certain embodiments, the disorder is systemic lupus erythematosus,scleroderma, Sjogren's syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, or myasthenia gravis.

Still other collections of medical disorders for treatment includeasthma, autoimmune diseases, cancers, ciliopathies, cleft palate,diabetes, heart disease, hypertension, inflammatory bowel disease,mental retardation, mood disorder, obesity, refractive error,infertility, Angelman syndrome, celiac disease, Charcot-Marie-Toothdisease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis,hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria,polycystic kidney disease, (PKD1 or PKD2), Prader-Willi syndrome,sickle-cell disease, Tay-Sachs disease, Turner syndrome, Alzheimer'sdisease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexianervosa, anxiety disorder, atherosclerosis, attention deficithyperactivity disorder, autism, bipolar disorder, chronic fatiguesyndrome, chronic obstructive pulmonary disease, Crohn's disease,coronary heart disease, dementia, depression, diabetes mellitus type 1,diabetes mellitus type 2, epilepsy. Guillain-Barre syndrome, irritablebowel syndrome, lupus, metabolic syndrome, multiple sclerosis,myocardial infarction, obesity, obsessive-compulsive disorder, panicdisorder, Parkinson's disease, psoriasis, rheumatoid arthritis,sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourettesyndrome, vasculitis, aceruloplasminemia, achondrogenesis type II,achondroplasia, acrocephaly. Gaucher disease type 2, acute intermittentporphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratasedeficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome,adrenoleukodystrophy, ALA-D porphyria, alkaptonuria, Alexander disease,alkaptonuric ochronosis, alpha-1 antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstromsyndrome, amelogenesis imperfecta, Anderson-Fabry disease, androgeninsensitivity syndrome, anemia, angiokeratoma corporis diffusum,angiomatosis retinae (von Hippel-Lindau disease), Apert syndrome,arachnodactyly (Marfan syndrome), Stickler syndrome, arthrochalasismultiplex congenita (Ehlers-Danlos syndrome#arthrochalasia type), ataxiatelangiectasia (Louis-Bar syndrome), Rett syndrome, primary pulmonaryhypertension, Sandhoff disease, neurofibromatosis type II,Beare-Stevenson cutis gyrata syndrome, Mediterranean fever, familialBenjamin syndrome, beta-thalassemia, bilateral acousticneurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis),Creuzfel-jakob disease, Birt-Hogg-Dube syndrome, brittle bone disease(osteogenesis imperfecta), Rubinstein-Taybi syndrome, bronzediabetes/bronzed cirrhosis (hemochromatosis), bulbospinal muscularatrophy (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipasedeficiency), chronic granulomatous disorder (CGD), campomelic dysplasia,biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri du chatsyndrome, CAVD (congenital absence of the vas deferens), CBAVD(congenital bilateral absence of the vas deferens), Cayler cardiofacialsyndrome, CEP (congenital erythropoietic porphyria), cystic fibrosis,congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia),otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia,Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome,Cockayne syndrome (familial adenomatous polyposis), congenitalerythropoietic porphyria, congenital heart disease,methemoglobinemia/congenital methemoglobinaemia, achondroplasia,connective tissue disease, conotruncal anomaly face syndrome, Cooley'sanemia (beta-thalassemia), copper storage disease (Wilson's disease),copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Curschmann-Batten-Steinertsyndrome (myotonic dystrophy), primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophyDuchenne and Becker types (DBMD), Usher syndrome, degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome,dihydrotestosterone receptor deficiency, Down syndrome, dwarfism,erythropoietic protoporphyria, erythroid 5-aminolevulinate synthetasedeficiency, erythropoietic porphyria, erythropoietic uroporphyria,Friedreich's ataxia, familial paroxysmal polyserositis, porphyriacutanea tarda, familial pressure sensitive neuropathy, fibrocysticdisease of the pancreas, fragile X syndrome, genetic brain disorders,giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandbergsyndrome (pseudoxanthoma elasticum), Gunther disease (congenitalerythropoietic porphyria), Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), hyperandrogenism, hypochondroplasia,hypochromic anemia, immune system disorders, Insley-Astley syndrome,Jackson-Weiss syndrome, Joubert syndrome, kidney diseases, includinghyperoxaluria, Kniest dysplasia, lacunar dementia, Langer-Saldinoachondrogenesis, Lynch syndrome, lysyl-hydroxylase deficiency,Machado-Joseph disease, metabolic disorders, movement disorders,Mowat-Wilson syndrome, Muenke syndrome, multiple neurofibromatosis,Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemmam-Pickdisease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease,Peutz-Jeghers syndrome, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), primary senile degenerative dementia, progeria(Hutchinson-Gilford progeria syndrome), progressive chorea, progressivemuscular atrophy, spinal muscular atrophy, propionic acidemia, proximalmyotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthomaelasticum), Rb (retinoblastoma), Recklinghausen disease(neurofibromatosis type I), recurrent polyserositis, retinal disorders,retinoblastoma, RFALS type 3, Ricker syndrome, Riley-Day syndrome,Roussy-Levy syndrome, severe achondroplasia with developmental delay andacanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast,leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberosa(tuberous sclerosis), SDAT, SEDc (spondyloepiphyseal dysplasiacongenita), Shprintzen-Goldberg syndrome, skin pigmentation disorders,Smith-Lemli-Opitz syndrome, South-African genetic porphyria (variegateporphyria), infantile-onset ascending hereditary spastic paralysis,speech and communication disorders, sphingolipidosis, spinocerebellarataxia, stroke, tetrahydrobiopterin deficiency, thyroid disease,tomaculous neuropathy (hereditary neuropathy with liability to pressurepalsies), Treacher-Collins syndrome, triplo X syndrome (triple Xsyndrome), trisomy 21 (Down syndrome), trisomy X, vision impairment andblindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome,Warburg-Sjo-Fledelius syndrome, Weissenbacher-Zweymuller syndrome,Wolf-Hirschhom syndrome, Wolff periodic disease, or xerodermapigmentosum. In certain embodiments, the disorder for treatment is acancer (e.g., a squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, renal cell carcinoma; cancerof the bladder, bowel, breast, cervix, colon, esophagus, head, kidney,liver, lung, neck, ovary, pancreas, prostate, and stomach; a leukemia; abenign or malignant lymphoma; a benign or malignant melanoma; amyeloproliferative disease; a sarcoma; uterine cancer, testicularcancer, thyroid cancer, astrocytoma, melanoma; carcinosarcoma, Hodgkin'sdisease, Wilms' tumor, or a teratocarcinoma).

Another aspect of the invention provides a method of treating orpreventing a disease characterized by oxidative stress. The methodcomprises administering to a patient in need thereof adeuterium-enriched compound described herein to treat or prevent thedisease characterized by oxidative stress. Exemplary diseasescharacterized by oxidative stress include, for example, cancer, ahyperproliferative cell growth condition, Parkinson's disease,Alzheimer's disease, atherosclerosis, heart failure (includingcongestive heart failure), myocardial infarction, schizophrenia, bipolardisorder, fragile X syndrome, sickle cell disease, chronic fatiguesyndrome, aging (including aging by induction of mitohormesis), diabetes(e.g., type I diabetes) and vascular disease.

Dosages

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, vary depending on factors suchas: specific indication to be treated; age and condition of a patient;and amount of second active agent used, if any. Generally, a compoundprovided herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

Second Active Agents

A compound provided herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions provided herein. Certain combinations may worksynergistically in the treatment of particular types of diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, can also work to alleviateadverse effects associated with certain second active agents, and viceversa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransferase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCl); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Perjeta®)); PD-1 and PD-L1 inhibitors (suchas, for example, pembrolizumab (Keytruda®), nivolumab (Opdivo®),atezolizumab (Tecentriq®)); VEGFR antibodies (such as, for example,bevacizumab (Avastin®)); VEGFR inhibitors (such as, for example, Flk-1specific kinase inhibitors, SU5416 and PTK787/ZK222584); PI3K inhibitors(such as, for example, wortmannin); C-Met inhibitors (such as, forexample, PHA-665752); monoclonal antibodies (such as, for example,rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) andG250); and anti-TNF-α antibodies. Examples of small molecule activeagents include, but are not limited to, anticancer agents andantibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated.

For instance, for the treatment of cancer, second active agents include,but are not limited to: semaxanib; cyclosporin; etanercept; doxycycline;bortezomib; acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; albomycin; ametantrone acetate;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycinsulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib; chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitotane; mitoxantrone hydrochloride; mycophenolic acid;nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozotocin; sulofenur; talisomycin; tecogalan sodium;taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide;teroxirone; testolactone; thiamiprine; thioguanine; thiotepa;tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to:20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogens;antiestrogens; antineoplaston; antisense oligonucleotides; aphidicolinglycinate; apoptosis gene modulators; apoptosis regulators; apurinicacid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; bortezomib (Velcade®); breflate; bropirimine;budotitane; buthionine sulfoximine; calcipotriol; calphostin C;camptothecin derivatives; capecitabine; carboxyamidotriazole;cartilage-derived angiogenesis inhibitor; carzelesin; casein kinaseinhibitors; castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin-816;crisnatol; cryptophycin-8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; docetaxel; docosanol;dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; etanidazole;etoposide phosphate; everolimus (Zortress®); exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorubicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;ibrutinib (Imbruvica®); idarubicin; idelalisib (Zydelig®); idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole;isohomohalichondrin B; itasetron; ixazomib (Ninlaro®); jasplakinolide;kahalalide F; lamellarin N triacetate; lanreotide; leinamycin;lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemiainhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maytansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;fibroblast growth factor-saporin mitotoxin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryllipid A+myobacterium cell wall skeleton; mopidamol; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; Nitrullyn; oblimersen (Genasense®);O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron hydrochloride; oracin; oral cytokine inducer;ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxelanalogues; paclitaxel derivatives; palau'amine; palbociclib (Ibrance®);palmitoylrhizoxin; pamidronic acid; panaxytriol; panobinostat(Farydak®); panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phosphataseinhibitors; picibanil; pilocarpine hydrochloride; pirarubicin;piritrexim; placetin A; placetin B; plasminogen activator inhibitor;platinum complex; platinum compounds; platinum-triamine complex;porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;prostaglandin J2; proteasome inhibitors; protein A-based immunemodulator; protein kinase C inhibitor; microalgal protein kinase Cinhibitors; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylatedhemoglobin polyoxyethylene conjugate; Raf antagonists; raltitrexed;ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors;Ras-GAP inhibitor; demethylated retelliptine; rhenium-186 etidronate;rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;rubiginone B1; ruboxyl; ruxolitinib (Jakafi®); safingol; saintopin;SarCNU; sarcophytol A; sargramostim; SDI-1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin-binding protein; sonermin;sorafenib (Nexavar®); sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorinostat (Zolinza®);vorozole; zanoterone; zeniplatin; zilascorb(2H); and zinostatinstimalamer.

Yet other specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatin, temozolomide (Temodar®),cyclophosphamide, carboplatin, procarbazine, Gliadel®, tamoxifen,topotecan, methotrexate, Taxol®, taxotere, fluorouracil, leucovorin,irinotecan, Xeloda®, CPT-11, interferon alpha, pegylated interferonalpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa,fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol,paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine,zoledronic acid, pamitronate, Biaxin®, busulfan, prednisone,bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®),paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate(Emcyt®), sulindac, and etoposide.

In another aspect, examples of specific second agents according to theindications to be treated can be found in the following references, allof which are incorporated herein in their entireties: U.S. Pat. Nos.6,281,230 and 5,635,517; U.S. Patent Publication Nos. 2004/0220144,2004/0087546, 2005/0203142, 2004/0091455, 2005/0100529, 2005/0214328,2005/0239842, 2006/0154880, 2006/0122228, 2005/0143344, and2006/0188475.

Examples of second active agents that may be used for the treatment ofpain include, but are not limited to, conventional therapeutics used totreat or prevent pain such as antidepressants, anticonvulsants,antihypertensives, anxiolytics, calcium channel blockers, musclerelaxants, non-narcotic analgesics, opioid analgesics,anti-inflammatories, COX-2 inhibitors, immunomodulatory agents,alpha-adrenergic receptor agonists or antagonists, immunosuppressiveagents, corticosteroids, hyperbaric oxygen, ketamine, other anestheticagents, NMDA antagonists, and other therapeutics found, for example, inthe Physician's Desk Reference 2003. Specific examples include, but arenot limited to, salicylic acid acetate (Aspirin®), celecoxib(Celebrex®), Enbrel®, ketamine, gabapentin (Neurontin®), phenytoin(Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®),valproic acid (Depakene®), morphine sulfate, hydromorphone, prednisone,griseofulvin, penthonium, alendronate, diphenhydramine, guanethidine,ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO),clonidine (Catapres®), bretylium, ketanserin, reserpine, droperidol,atropine, phentolamine, bupivacaine, lidocaine, acetaminophen,nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine(Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®), fluoxetine(Prozac®), sertraline (Zoloft®), naproxen, nefazodone (Serzone®),venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®),mexiletine, nifedipine, propranolol, tramadol, lamotrigine, rofecoxib(Vioxx®), ziconotide, ketamine, dextromethorphan, benzodiazepines,baclofen, tizanidine, and phenoxybenzamine.

Examples of second active agents that may be used for the treatment ofmacular degeneration and related syndromes include, but are not limitedto, a steroid, a light sensitizer, an integrin, an antioxidant, aninterferon, a xanthine derivative, a growth hormone, a neutrotrophicfactor, a regulator of neovascularization, an anti-VEGF antibody, aprostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatorycompound or an antiangiogenesis compound, or a combination thereof.Specific examples include, but are not limited to, verteporfin,purlytin, an angiostatic steroid, rhuFab, interferon-2-alpha,pentoxifylline, tin etiopurpurin, ranibizumab (Lucentis®), lutetiumchelates such as motexafin lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin,6′-O-Mal-genistin, 6′-O—Ac-genistin, daidzein, daidzin,6′-O-Mal-daidzin, 6′-O—Ac-daidzin, glycitein, glycitin,6′-O-Mal-glycitin, biochanin A, formononetin (U.S. Pat. No. 6,001,368),triamcinolone acetonide, dexamethasone (U.S. Pat. No. 5,770,589),thalidomide, glutathione (U.S. Pat. No. 5,632,984), basic fibroblastgrowth factor (bFGF), transforming growth factor b (TGF-b),brain-derived neurotrophic factor (BDNF), plasminogen activator factortype 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly),Miravant SnET2, and Retisert™ implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment ofskin diseases include, but are not limited to, keratolytics, retinoids,α-hydroxy acids, antibiotics, collagen, botulinum toxin, interferon,steroids, and immunomodulatory agents. Specific examples include, butare not limited to, 5-fluorouracil, masoprocol, trichloroacetic acid,salicylic acid, lactic acid, ammonium lactate, urea, tretinoin,isotretinoin, antibiotics, collagen, botulinum toxin, interferon,corticosteroid, transretinoic acid and collagens such as human placentalcollagen, animal placental collagen, Dermalogen®, AlloDerm®, Cymetra®,Autologen®, Zyderm®, Zyplast®, Resoplast®, and Isolagen®.

Examples of second active agents that may be used for the treatment ofpulmonary hypertension and related disorders include, but are notlimited to, anticoagulants, diuretics, cardiac glycosides,calcium-channel blockers, vasodilators, prostacyclin analogues,endothelin antagonists, phosphodiesterase inhibitors (e.g., PDE Vinhibitors), endopeptidase inhibitors, lipid-lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PGI2)), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat(Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin,L-arginine, iloprost, beraprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment ofasbestos-related disorders include, but are not limited to,anthracycline, platinum, alkylating agents, oblimersen (Genasense®),cyclophosphamide, Temodar®, carboplatin, procarbazine, Gliadel®,tamoxifen, topotecan, methotrexate, taxotere, irinotecan, capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxel, paclitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, pamidronate, Biaxin®,busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), ganciclovir, adriamycin, bleomycin, hyaluronidase,mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment ofparasitic diseases include, but are not limited to, chloroquine,quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline,clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquine,proguanil, atovaquone, azithromycin, suramin, pentamidine, melarsoprol,nifurtimox, benznidazole, amphotericin B, pentavalent antimony compounds(e.g., sodium stibogluconate), interferon gamma, itraconazole, acombination of dead promastigotes and BCG, leucovorin, corticosteroids,sulfonamide, spiramycin, IgG (serology), trimethoprim, andsulfamethoxazole.

Examples of second active agents that may be used for the treatment ofimmunodeficiency disorders include, but are not limited to: antibiotics(therapeutic or prophylactic) such as, but not limited to, ampicillin,tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, anderythromycin; antivirals such as, but not limited to, amantadine,rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma;immunologic enhancing drugs such as, but not limited to, levamisole andisoprinosine; biologics such as, but not limited to, gammaglobulin,transfer factor, interleukins, and interferons; hormones such as, butnot limited to, thymic hormones; and other immunologic agents such as,but not limited to, B cell stimulators (e.g., BAFF/BlyS), cytokines(e.g., IL-2, IL-4, and IL-5), growth factors (e.g., TGF-α), antibodies(e.g., anti-CD40 and IgM), oligonucleotides containing unmethylated CpGmotifs, and vaccines (e.g., viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment ofCNS disorders include, but are not limited to: opioids; a dopamineagonist or antagonist, such as, but are not limited to, Levodopa,L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine,benzatropine, pargyline, fenoldopam mesylate, cabergoline, pramipexoledihydrochloride, ropinirole, amantadine hydrochloride (Symmetrel®),selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet® CR; aMAO inhibitor, such as, but not limited to, iproniazid, clorgiline,phenelzine and isocarboxazid; a COMT inhibitor, such as, but not limitedto, tolcapone and entacapone; a cholinesterase inhibitor, such as, butnot limited to, physostigmine salicylate, physostigmine sulfate,physostigmine bromide, neostigmine bromide, neostigmine methylsulfate,ambenonium chloride, edrophonium chloride, tacrine, pralidoximechloride, obidoxime chloride, trimedoxime bromide, diacetyl monoxime,pyridostigmine, and demecarium bromide; an anti-inflammatory agent, suchas, but not limited to, naproxen sodium, diclofenac sodium, diclofenacpotassium, celecoxib, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, rofecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenolate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbiprofen, oxaprozin, piroxicam, ampiroxicam, droxicam,pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine,aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate,auranofin, methotrexate, colchicine, allopurinol, probenecid,sulfinpyrazone and benzbromarone or betamethasone and otherglucocorticoids; and an antiemetic agent, such as, but not limited to,metoclopramide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and a mixture thereof.

Examples of second active agents that may be used for the treatment ofCNS injuries and related syndromes include, but are not limited to,immunomodulatory agents, immunosuppressive agents, antihypertensives,anticonvulsants, fibrinolytic agents, antiplatelet agents,antipsychotics, antidepressants, benzodiazepines, buspirone, amantadine,and other known or conventional agents used in patients with CNSinjury/damage and related syndromes. Specific examples include, but arenot limited to: steroids (e.g., glucocorticoids, such as, but notlimited to, methylprednisolone, dexamethasone and betamethasone);anti-inflammatory agents, including, but not limited to, naproxensodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac,oxaprozin, diflunisal, etodolac, ibuprofen, ketoprofen, nabumetone,rofecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenolate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, diclofenac, flurbiprofen,piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam,phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone,zileuton, aurothioglucose, gold sodium thiomalate, auranofin,colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone;cAMP analogs including, but not limited to, db-cAMP; an agent comprisinga methylphenidate drug, which comprises 1-threo-methylphenidate,d-threo-methylphenidate, dl-threo-methylphenidate,l-erythro-methylphenidate, d-erythro-methylphenidate,dl-erythro-methylphenidate, and a mixture thereof; and a diuretic agentsuch as, but not limited to, mannitol, furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment ofdysfunctional sleep and related syndromes include, but are not limitedto, a tricyclic antidepressant agent, a selective serotonin reuptakeinhibitor, an antiepileptic agent (gabapentin, pregabalin,carbamazepine, oxcarbazepine, levetiracetam, topiramate), anantiaryhthmic agent, a sodium channel blocking agent, a selectiveinflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin®, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzatropine, pargyline,fenoldopam mesylate, cabergoline, pramipexole dihydrochloride,ropinirole, amantadine hydrochloride (Symmetrel®), selegilinehydrochloride, carbidopa, pergolide mesylate, Sinemet® CR, iproniazid,clorgiline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine salicylate, physostigmine sulfate, physostigmine bromide,neostigmine bromide, neostigmine methylsulfate, ambenonium chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxime, pyridostigmine, demecariumbromide, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, ibuprofen,ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenolate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac,flurbiprofen, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopramide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment ofhemoglobinopathy and related disorders include, but are not limited to:interleukins, such as IL-2 (including recombinant IL-2 (“r1L2”) andcanarypox IL-2), IL-10, IL-12, and IL-18; interferons, such asinterferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferonalfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;hydroxyurea; butyrate or butyrate derivatives; nitrous oxide;hydroxyurea; Nicosan (see U.S. Pat. No. 5,800,819); Gardos channelantagonists such as clotrimazole and triaryl methane derivatives;deferoxamine; protein C; and transfusions of blood, or of a bloodsubstitute such as Hemospan® or Hemospan® PS (Sangart).

In other embodiments, the second active agent may be one of thefollowing: (i) an immune checkpoint inhibitor (e.g., an inhibitor ofPD-1, PD-L1, CD28, CTLA-4, SLAMF7, or KIR), (ii) an HDAC inhibitor,(iii) a kinase inhibitor (e.g., mTOR inhibitor, Bcr-Abl inhibitor, orPIM inhibitor), (iv) proteasome inhibitor, (v) cyclin-dependent kinaseinhibitor (e.g., inhibitor of CDK-4 or CDK-6), (vi) non-receptor kinaseinhibitor (e.g., inhibitor of JAK1, JAK2, or BTK), or (vii) a B-cellmodulator (e.g., CD20 inhibitor or CD38 inhibitor).

In yet other embodiments, the second active agent is one of thefollowing or a pharmaceutically acceptable salt thereof: ibrutinib,ricolinostat (ACY-1215), carfilzomib, oprozomib, durvalumab, sorafenib,rituximab, dasatinib, ulocuplumab (BMS-936564), ipilimumab, nivolumab,elotuzumab, BMS-833923, lirilumab (IPH2102/BMS-986015), CC-223, CC-292,idelalisib, daratumumab, abemaciclib, LY2835219, pidilizumab,azacitidine, vorinostat, pembrolizumab, MK-3475, MOR03087 (MOR202),panobinostat, everolimus, PDR001, PIM447, CTL019, ofatumumab,ruxolitinib, demcizumab, crizotinib, palbociclib, avelumab, REGN2810,atezolizumab, obinutuzumab, isatuximab (SAR650984), bortezomib,ixazomib, and REGN1979.

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, and the second activeagents to a patient can occur simultaneously or sequentially by the sameor different routes of administration. The suitability of a particularroute of administration employed for a particular active agent willdepend on the active agent itself (e.g., whether it can be administeredorally without decomposing prior to entering the blood stream) and thedisease being treated. One route of administration for compoundsprovided herein is oral. Routes of administration for the second activeagents or ingredients are known to those of ordinary skill in the art.See, e.g., Physicians' Desk Reference (60^(th) Ed., 2006).

In another aspect, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated, the severity and stage of disease, and theamount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

Cycling Therapy

In certain aspects, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in another aspect, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another aspect encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another aspect, a compound provided herein isadministered for a greater number of cycles than would typically causedose-limiting toxicity in a patient to whom a second active ingredientis not also being administered.

In another aspect, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In another aspect, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another aspect, thecombination of a compound provided herein and a second active ingredientis administered by intravenous infusion over about 90 minutes everycycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all aspects of the invention maybe taken in conjunction with any other aspect or aspects to describeadditional aspects. It is also to be understood that each individualelement of the aspects is intended to be taken individually as its ownindependent aspect. Furthermore, any element of an aspect is meant to becombined with any and all other elements from any aspect to describe anadditional aspect.

Manufacture of Medicaments

Another aspect of the invention provides for the use of adeuterium-enriched compound described herein for the manufacture of amedicament. The medicament may be for treating one or more of themedical disorders described herein, such as cancer.

III. Dosing Considerations and Combination Therapy

Doses of a compound provided herein, or a pharmaceutically acceptablesalt thereof, vary depending on factors such as: specific indication tobe treated; age and condition of a patient; and amount of second activeagent used, if any. Generally, a compound provided herein, or apharmaceutically acceptable salt thereof, may be used in an amount offrom about 0.1 mg to about 1 g per day, or from about 0.1 mg to about500 mg per day, and can be adjusted in a conventional fashion (e.g., thesame amount administered each day of the treatment), in cycles (e.g.,one week on, one week off), or in an amount that increases or decreasesover the course of treatment. In other embodiments, the dose can be fromabout 1 mg to 1000 mg, from about 1 mg to about 450 mg, from about 0.1mg to about 150 mg, from about 1 mg to about 300 mg, from about 10 mg toabout 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg,or from about 1 mg to about 20 mg.

In certain aspects, the therapeutic agents provided herein arecyclically administered to a patient. Cycling therapy involves theadministration of an active agent for a period of time, followed by arest (i.e., discontinuation of the administration) for a period of time,and repeating this sequential administration. Cycling therapy can reducethe development of resistance to one or more of the therapies. Theseregimens can avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in another aspect, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another aspect encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another aspect, a compound provided herein isadministered for a greater number of cycles than would typically causedose-limiting toxicity in a patient to whom a second active ingredientis not also being administered.

In another aspect, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 1000 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 450 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 300 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In another aspect, a compound provided herein and a second activeingredient are administered orally or parenterally, with administrationof the compound provided herein occurring prior to (e.g., about 30 to 60minutes) the second active ingredient, during a cycle of four to sixweeks. In certain embodiments, the compound and second active agent areadministered as a single dosage or they are administered separately. Inanother aspect, the combination of a compound provided herein and asecond active ingredient is administered by intravenous infusion overabout 90 minutes every cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about three to about fourcycles.

Combination Therapy

A compound provided herein, or a pharmaceutically acceptable saltthereof, can be combined with other pharmacologically active compounds(“second active agents”) in methods and compositions provided herein.Certain combinations may work synergistically in the treatment ofparticular types of diseases or disorders, and conditions and symptomsassociated with such diseases or disorders. A compound provided herein,or a pharmaceutically acceptable salt thereof, can also work toalleviate adverse effects associated with certain second active agents,and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

IV. Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising adeuterium-enriched compound described herein and a pharmaceuticallyacceptable carrier. In certain embodiments, the pharmaceuticalcompositions comprise a therapeutically-effective amount of adeuterium-enriched compound described herein, formulated together withone or more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets (e.g., those targeted for buccal,sublingual, and/or systemic absorption), boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration by,for example, subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt thereof. Pharmaceutical compositionsand dosage forms can further comprise one or more excipients.Additionally, pharmaceutical compositions and dosage forms providedherein can comprise one or more additional active ingredients. Examplesof optional second, or additional, active ingredients are describedabove.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18^(th) Ed., MackPublishing, Easton Pa. (1990).

The suitability of a particular excipient may depend on the specificactive ingredients in the dosage form. For example, the decomposition ofsome active ingredients may be accelerated by some excipients such aslactose, or when exposed to water. Active ingredients that compriseprimary or secondary amines are particularly susceptible to suchaccelerated decomposition. Consequently, provided are pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or disaccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U. S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In another aspect,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients. Anhydrous pharmaceutical compositions anddosage forms can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms that comprise lactose and at least oneactive ingredient that comprises a primary or secondary amine arepreferably anhydrous if substantial contact with moisture and/orhumidity during manufacturing, packaging, and/or storage is expected. Ananhydrous pharmaceutical composition should be prepared and stored suchthat its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in another aspect, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, dose containers (e.g.,vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In another aspect, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg.Examples of dosages include, but are not limited to, 0.1, 1, 2, 5, 7.5,10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450,or 500 mg.

In another aspect, dosage forms comprise the second active ingredient inan amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated, and theamount(s) of a compound provided herein, and any optional additionalactive agents concurrently administered to the patient.

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18^(th) Ed., Mack Publishing, Easton Pa.(1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In another aspect, the invention provides oral dosage forms that aretablets or capsules, in which case solid excipients are employed. Inanother aspect, the tablets can be coated by standard aqueous ornon-aqueous techniques. Such dosage forms can be prepared by any of themethods of pharmacy. In general, pharmaceutical compositions and dosageforms are prepared by uniformly and intimately admixing the activeingredients with liquid carriers, finely divided solid carriers, orboth, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in anotheraspect, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. Inanother aspect, pharmaceutical compositions comprise from about 0.5 toabout 15 weight percent of disintegrant, or from about 1 to about 5weight percent of disintegrant. Disintegrants that can be used inpharmaceutical compositions and dosage forms include, but are notlimited to, agar-agar, alginic acid, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, crospovidone, polacrilin potassium,sodium starch glycolate, potato or tapioca starch, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof.Additional lubricants include, for example, a Syloid® silica gel(AEROSIL200, manufactured by W. R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPiano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In another aspect, the invention provides a solid oral dosage formcomprising a compound provided herein, anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

Active ingredients provided herein can also be administered bycontrolled release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated in its entirety herein by reference. Such dosage formscan be used to provide slow or controlled-release of one or more activeingredients using, for example, hydroxypropyl methyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active agents provided herein. In anotheraspect, the invention provides single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial.Administration of a parenteral dosage form bypasses a patient's naturaldefenses against contaminants, and thus, in these aspects, parenteraldosage forms are sterile or capable of being sterilized prior toadministration to a patient. Examples of parenteral dosage formsinclude, but are not limited to, solutions ready for injection, dryproducts ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions. Suitable vehicles that can be used to provide parenteraldosage forms are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated in itsentirety herein by reference.

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18^(th) Eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4^(th) Ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In another aspect,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are nontoxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16^(th) and 18^(th) Eds., Mack Publishing,Easton Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other aspects, stearates can serve as a lipidvehicle for the formulation, as an emulsifying agent or surfactant, oras a delivery-enhancing or penetration-enhancing agent. In otheraspects, salts of the active ingredients can be used to further adjustthe properties of the resulting composition.

In another aspect, the active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another aspect, provided are kits which can simplifythe administration of appropriate amounts of active ingredients.

In another aspect, the invention provides a kit comprising a dosage formof a compound provided herein. Kits can further comprise additionalactive ingredients or a pharmacologically active mutant or derivativethereof, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein.

In other aspects, the kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

V. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The term “compound” refers to a quantity of molecules that is sufficientto be weighed, tested for its structural identity, and to have ademonstrable use (e.g., a quantity that can be shown to be active in anassay, an in vitro test, or in vivo test, or a quantity that can beadministered to a patient and provide a therapeutic benefit).

Unless indicated otherwise, when a D is specifically recited at aposition or is shown in a formula, this D represents a mixture ofhydrogen and deuterium where the amount of deuterium is about 100%(i.e., the abundance of deuterium ranges from greater than 90% up to100%). In certain embodiments, the abundance of deuterium in D is from95% to 100%, or from 97% to 100%.

The term “patient” refers to organisms to be treated by the methods ofthe present invention. Such organisms preferably include, but are notlimited to, mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and most preferably includes humans.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

“Therapeutically effective amount” includes an amount of a compound ofthe invention that is effective when administered alone or incombination to treat the desired condition or disorder. “Therapeuticallyeffective amount” includes an amount of the combination of compoundsclaimed that is effective to treat the desired condition or disorder.The combination of compounds can be additive and is preferably asynergistic combination. Synergy, as described, for example, by Chou andTalalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect ofthe compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower incidence of adverse side effects and/or toxicity, increasedefficacy, or some other beneficial effect of the combination comparedwith the individual components.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofthe basic residues. The pharmaceutically acceptable salts include theconventional quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. These salts canbe prepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed during subsequent purification.For example, such conventional non-toxic salts include, but are notlimited to, those derived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, bisulfonic, carbonic,citric, edetic, ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauric, lauryl sulfonic, maleic, malic,mandelic, methanesulfonic, napsylic, naphthylic, nitric, oleic, oxalic,palmitic, pamoic, pantothenic, phenylacetic, phosphoric,polygalacturonic, propionic, salicylic, stearic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and valeric.(See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm.Sci. 66:1-19.). In certain embodiments, the pharmaceutically acceptablesalt is a hydrochloric acid salt. In certain other embodiments, thepharmaceutically acceptable salt is a hydrobromic acid salt.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as oil/water orwater/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see e.g., Martin,Remington's Pharmaceutical Sciences, 15^(th) Ed., Mack Publ. Co.,Easton, Pa. (1975).

The term “alkyl” refers to a saturated straight or branched hydrocarbon,such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms,referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, etc.

The term “alkylene” refers to a diradical of an alkyl group. Exemplaryalkylene groups include —CH₂—, —CH₂CH₂—, and —CH₂C(H)(CH₃)CH₂—.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₃-C₆ cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl,cyclopentyl, cyclobutyl, and cyclopropyl.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. Exemplary haloalkyl groups include —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CF₂CF₃, and the like.

The term “hydroxyalkyl” refers to an alkyl group that is substitutedwith at least one hydroxyl. Exemplary hydroxyalkyl groups include—CH₂CH₂OH, —C(H)(OH)CH₃, —CH₂C(H)(OH)CH₂CH₂OH, and the like.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Exemplary aralkyl groups include

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with, for example, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl,—CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido,sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic aromatic ring systems having two or more carbocyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein all of the fused rings are aromatic rings,e.g., in a naphthyl group.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms (e.g., O, N,and S). Representative examples of heteroaryl groups include pyrrolyl,furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and thelike. Unless specified otherwise, the heteroaryl ring may be substitutedat one or more ring positions with, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. The term “heteroaryl” also includes polycyclicaromatic ring systems having two or more rings in which two or more ringatoms are common to two adjoining rings (the rings are “fused rings”)wherein all of the fused rings are heteroaromatic, e.g., in anaphthyridinyl group. In certain embodiments, the heteroaryl is a 5-6membered monocyclic ring or a 9-10 membered bicyclic ring.

The terms ortho, meta, and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

As used herein, the terms “heterocyclic” and “heterocyclyl” represent,for example, an aromatic or nonaromatic ring (e.g., a monocyclic orbicyclic ring) containing one or more heteroatoms. The heteroatoms canbe the same or different from each other. Examples of heteroatomsinclude, but are not limited to nitrogen, oxygen and sulfur. Aromaticand nonaromatic heterocyclic rings are well-known in the art. Somenonlimiting examples of aromatic heterocyclic rings include, but are notlimited to, pyridine, pyrimidine, indole, purine, quinoline andisoquinoline. Nonlimiting examples of nonaromatic heterocyclic compoundsinclude, but are not limited to, piperidine, piperazine, morpholine,pyrrolidine and pyrazolidine. Examples of oxygen containing heterocyclicrings include, but are not limited to, furan, oxirane, 2H-pyran,4H-pyran, 2H-chromene, benzofuran, and 2,3-dihydrobenzo[b][1,4]dioxine.Examples of sulfur-containing heterocyclic rings include, but are notlimited to, thiophene, benzothiophene, and parathiazine. Examples ofnitrogen containing rings include, but are not limited to, pyrrole,pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline,imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine,indole, purine, benzimidazole, quinoline, isoquinoline, triazole, andtriazine. Examples of heterocyclic rings containing two differentheteroatoms include, but are not limited to, phenothiazine, morpholine,parathiazine, oxazine, oxazole, thiazine, and thiazole. The heterocyclicring is optionally further substituted at one or more ring positionswith, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl, alkylthio,sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Incertain embodiments, the heterocyclyl group is a 3-7 membered ring that,unless specified otherwise, is substituted or unsubstituted.

The term “heterocycloalkyl” refers to a saturated heterocyclyl grouphaving, for example, 3-7 ring atoms (e.g., O, N, or S).

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(m)—R⁶¹, or R⁵⁰ and R⁵¹, taken togetherwith the N atom to which they are attached complete a heterocycle havingfrom 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In certain embodiments, only oneof R⁵⁰ or R⁵¹ may be a carbonyl, e.g., R⁵⁰, R⁵¹ and the nitrogentogether do not form an imide. In other embodiments, R⁵⁰ and R⁵¹ (andoptionally R⁵²) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of O-alkyl, —O-alkenyl, —O-alkynyl, and—O—(CH₂)_(m)—R⁶¹, where m and R⁶¹ are described above.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane substituted with an oxo group is cyclopentanone.

The symbol “

” indicates a point of attachment.

The term “substituted” means that one or more hydrogens on the atoms ofthe designated group are replaced with a selection from the indicatedgroup, provided that the atoms' normal valencies under the existingcircumstances are not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Theterms “stable compound” or “stable structure” refer to a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When any substituent or variable occurs more than one time in anyconstituent or the compound of the invention, its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

As a general matter, if a variable is not accompanied by a definition,then the previous definition of the variable controls.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

Finally, the invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects and embodiments of theinvention noted herein. It is understood that any and all aspects of theinvention may be taken in conjunction with any other aspects and/orembodiments to describe additional aspects. It is also to be understoodthat each individual element of the aspects is intended to be takenindividually as its own independent aspect. Furthermore, any element ofan aspect is meant to be combined with any and all other elements fromany aspect to describe an additional aspect.

INCORPORATION BY REFERENCE

All references listed herein are individually incorporated in theirentirety by reference.

EQUIVALENTS

Numerous modifications and variations of the invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise that as specifically described herein.

The invention claimed is:
 1. A deuterium-enriched compound of Formula I:

or a pharmaceutically acceptable salt thereof wherein: Z is D; R^(I-1),R^(I-2), R^(I-3), R^(I-4), R^(I-5), R^(I-6), R^(I-7), R^(I-8), R^(I-9),R^(I-10), R^(I-11), R^(I-12) and R^(I-13) are independently H or D; R¹is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; R² and R³ are each halogen: where the substituents on R¹,when present, are one to three groups Q, where each Q is independentlyalkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —R⁴OR⁵, —R⁴—R⁴OR, —R⁴N(R⁶)(R⁷), —R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷),—R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹, or —R⁴S(O)_(t)R⁸; R⁴ representsindependently for each occurrence alkylene, alkenylene or a direct bond;R⁵ represents independently for each occurrence hydrogen, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl groups in R⁵ are each independently optionallysubstituted with 1-3 Q¹ groups, where each Q¹ is independently alkyl,haloalkyl or halo; R⁶ and R⁷ are selected as follows: i) R⁶ and R⁷ areeach independently hydrogen or alkyl; or ii) R⁶ and R⁷ are takentogether with the nitrogen atom to which they are attached to form a 5or 6-membered heterocyclyl or heteroaryl ring, optionally substitutedwith one or two halo, alkyl or haloalkyl; R⁸ is alkyl, haloalkyl, orhydroxyalkyl; R⁹ is alkyl or aryl; J is O or S; and t is 1 or
 2. 2. Thecompound of claim 1, wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z.
 3. The compound of claim 1, wherein thecompound is represented by Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z.
 4. The compound of claim 2, wherein thecompound has a stereochemical purity of at least 95% enantiomeric excessat the carbon atom bearing variable Z.
 5. The compound of claim 1,wherein R¹ is one of the following:

wherein any H in R¹ is optionally replaced with D.
 6. The compound ofclaim 2, wherein R¹ is one of the following:


7. The compound of claim 2, wherein R² and R³ are fluoro.
 8. Thecompound of claim 7, wherein R^(I-1) and R^(I-13) are H.
 9. The compoundof claim 8, wherein R^(I-2), R^(I-3), R^(I-4), and R^(I-5) are H. 10.The compound of claim 9, wherein R^(I-6), R^(I-7), R^(I-8), R^(I-9) areH.
 11. The compound of claim 1, wherein the compound is a compound inthe table below or a pharmaceutically acceptable salt thereof: No.Chemical Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18


12. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein any hydrogen atomis optionally replaced with D.
 13. The compound of claim 12, wherein thecompound is

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim12, wherein the compound is a compound in the table below or apharmaceutically acceptable salt thereof: No. Chemical Structure 1

  stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing D. 2

  stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing D.


15. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.